Germline mutations in the breast and ovarian cancer susceptibility gene, BRCA1, predispose carriers to dramatically elevated risks of breast and ovarian cancer. This suggests that BRCA1 plays an important role in the regulation of growth and differentiation of epithelial cells, particularly those which are hormonally responsive. Further studies of BRCA1 function will serve as a foundation for understanding how the absence or mutation of this molecule promotes carcinogenesis. As a first step towards this goal, they have analyzed the temporal and spatial pattern of Brca1 expression during normal mouse embryogenesis, in adult tissues, in the mammary gland during postnatal development, and in the mammary glands of mice whose levels of ovarian hormones have been experimentally manipulated. Their results support a role for Brca1 in the regulation of cell proliferation and differentiation in multiple tissues including mammary epithelial cells during puberty and early pregnancy. In addition, they have observed that Brca1 expression remains elevated in the mammary glands of parous mice as compared with age matched virgin controls. They hypothesize that BRCA1 plays a critical role in the regulation of cell growth and differentiation in the mammary epithelium and that it does so in a developmentally specific manner. Furthermore, they hypothesize that the parity-induced elevation in expression of this putative tumor suppressor gene may be involved in mediating the protective effect of an early first full term pregnancy on breast cancer risk. The goal of this research is to determine the mechanisms by which BRCA1 normally controls the proliferation and differentiation of mammary epithelial cells. The specific aims of this proposal are to: (1)Determine the role of Brca1 in mammary epithelial proliferation, differentiation and development; and (II) Determine the role of Brca1 in the parity-induced reduction of breast cancer risk. The overall approach described in this proposal is to: 1) characterize the regulation of Brca1 expression as a function of differentiation both in vivo in the mouse and in vitro in defined model systems of proliferation and differentiation; 2) determine the effect of Brca1 overexpression on the ability of the mammary epithelium to proliferate and differentiate in vitro and in vivo in transgenic mice; 3) determine the effect of abolishing Brca1 expression on the differentiation and development of the mammary epithelium in vivo; and 4) determine the contribution made by Brca1 towards the parity induced reduction in breast cancer risk. Ultimately, understanding the role played by BRCA1 in the regulation of these processes has the potential to lead to novel strategies for the prevention and treatment of breast cancer.